1. Field of the Invention
The present invention relates to a pharmaceutical composition for preventing or treating a disease or disorder associated with the expression of RANKL (receptor activator of NF-κB ligand), a method for inhibiting the expression of RANKL and a method for screening an antibody drug candidate to inhibit the expression of RANKL.
2. Description of the Related Art
The regulation of osteoclasts is vital for maintaining the balance in bone remodeling, i.e., bone resorption by osteoclasts and bone formation by osteoblasts, and thus is important in the treatment of bone disease. Bone-resorbing osteoclasts are derived from hematopoietic cells of the monocyte-macrophages lineage and differentiate into multinucleated cells through multiple processes.1,2 Osteoclast formation and activity are regulated by local factors and by stromal and osteoblast cells in the bone environment.3 Increases in osteoclast number and activity can be caused by systemic alterations, such as the up-regulation of osteotropic or osteoclastogenic factors or a deficiency of estrogen, and in turn cause bone disease, including rheumatoid arthritis (RA), periodontal disease, and osteoporosis.4,5 In particular, receptor activator of NF-κB ligand (RANKL), a member of the TNF family that is expressed on stromal and osteoblast cells, plays an essential role in osteoclast differentiation and function. Several inflammatory cytokines including TNF-α and IL-1 can induce RANKL expression on stromal and osteoblast cells, which plays an important role in the bone and cartilage destruction in RA.6 Thus, the regulation of RANKL expression is important for preventing bone disorders caused by increased osteoclast formation.
Chemokines are a superfamily of cytokines important in inflammation and immune responses. Chemokines can be divided into four main groups (C, CC, CXC, and CX3C) according to the presence of none, one, or three amino acids between the first two cysteine residues, respectively.7,8 Several chemokines promote bone resorption by inducing osteoclast formation and survival as well as by directly inducing the migration and adhesion of leukocytes.9,10 In particular, the expression of MIP-1α and MIP-1β in multiple myeloma cells enhances osteolytic lesions by enhancing osteoclast formation and bone resorption.11 IFN-γ-inducible protein 10 (IP-10) was initially identified as a chemokine induced by IFN-γ that is secreted by various cell types.12 IFN stimulus response element and κB sites in the IP-10 promoter are important for IFN-γ-induced expression.13 IP-10 binds the receptor CXCR3 (CXC chemokine receptor 3) and regulates immune responses through activation and recruitment of leukocytes, including T cells, eosinophils, and monocytes.14,15 Also, IP-10 has antitumor activity in vivo, which has been attributed to the recruitment of lymphocytes. However, the role of IP-10 in the aspect of bone resorption has not yet been reported.
RA, a chronic inflammatory disease, is characterized by excessive bone resorption in the inflamed joints that is initially promoted through the recruitment of activated T cells.16 Although it has been reported that many chemokines and inflammatory cytokines induce the infiltration of inflammatory cells into the synovium of inflamed joints and mediate inflammation,17,19 the etiology of RA remains unknown. IP-10-deficient mice do not respond to allogeneic or antigenic stimulation and have defective trafficking of T cells.20 IP-10 is expressed in many T cell-related inflammatory diseases, such as multiple sclerosis, atherosclerosis, and lichen planus.21-23 Furthermore, a recent study by Hanaoka et al. showed that IP-10 is elevated in the synovial fluids of RA patients.24 These results suggest that IP-10 plays an important role in T cell-related inflammation and in the recruitment of T cells to inflammatory sites.
Throughout this application, various patents and publications are referenced and citations are provided in parentheses. The disclosure of these patents and publications in their entities are hereby incorporated by references into this application in order to more fully describe this invention and the state of the art to which this invention pertains.